Metal-Phenolic Nanocloaks on Cancer Cells Potentiate STING Pathway Activation for Synergistic Cancer Immunotherapy.

Due to the presence of natural neoantigens, autologous tumor cells hold great promise as personalized therapeutic vaccines. Yet autologous tumor cell vaccines require multi-step production that frequently leads to the loss of immunoreactive antigens, causing insufficient immune activation and significantly hampering their clinical applications. Herein, we introduce a novel whole-cell cancer vaccine by cloaking cancer cells with lipopolysaccharide-decorated manganese(II)-phenolic networks (MnTA nanocloaks) to evoke tumor-specific immune response for highly efficacious synergistic cancer immunotherapy. The natural polyphenols coordinate with Mn2+ and immediately adhere to the surface of individual cancer cells, thereby forming a nanocloak and encapsulating tumor neoantigens. Subsequent decoration with lipopolysaccharide induces internalization by dendritic cells, where Mn2+ ions are released in the cytosol, further facilitating the activation of the stimulator of the interferon genes (STING) pathway. Highly effective tumor suppression was observed by combining the nanocloaked cancer cell treatment with anti-programmed cell death ligand 1 (anti-PD-L1) antibodies-mediated immune checkpoint blockade therapy. Our work demonstrates a universal yet simple strategy to engineer a cell-based nanobiohybrid system for enhanced cancer immunotherapy.

Systemic Tumor Suppression via Macrophage-Driven Automated Homing of Metal-Phenolic-Gated Nanosponges for Metastatic Melanoma.

Cell-based therapies comprising the administration of living cells to patients for direct therapeutic activities have experienced remarkable success in the clinic, of which macrophages hold great potential for targeted drug delivery due to their inherent chemotactic mobility and homing ability to tumors with high efficiency. However, such targeted delivery of drugs through cellular systems remains a significant challenge due to the complexity of balancing high drug-loading with high accumulations in solid tumors. Herein, a tumor-targeting cellular drug delivery system (MAGN) by surface engineering of tumor-homing macrophages (Mφs) with biologically responsive nanosponges is reported. The pores of the nanosponges are blocked with iron-tannic acid complexes that serve as gatekeepers by holding encapsulated drugs until reaching the acidic tumor microenvironment. Molecular dynamics simulations and interfacial force studies are performed to provide mechanistic insights into the "ON-OFF" gating effect of the polyphenol-based supramolecular gatekeepers on the nanosponge channels. The cellular chemotaxis of the Mφ carriers enabled efficient tumor-targeted delivery of drugs and systemic suppression of tumor burden and lung metastases in vivo. The findings suggest that the MAGN platform offers a versatile strategy to efficiently load therapeutic drugs to treat advanced metastatic cancers with a high loading capacity of various therapeutic drugs.

Multifunctional Dual Cross-Linked Bioadhesive Patch with Low Immunogenic Response and Wet Tissues Adhesion.

The development of bioadhesives is an important, yet challenging task as seemingly mutually exclusive properties need to be combined in one material, that is, strong adhesion, water resistance, and high biocompatibility. Here, a biocompatible and biodegradable protein-based bioadhesive patch (PBP) with high adhesion strength and low immunogenic response is reported. PBP exists as a strong adhesion for biological surfaces, which is higher than some conventional bioadhesives (i.e., polyethylene glycol and fibrin). Robust adhesion and strength are realized through the removal of interfacial water and fast formation of multiple supramolecular interactions induced by metal ions. The PBP's high biocompatibility is evaluated and immunogenic response in vitro and in vivo is neglected. The strong adhesion on soft biological tissues qualifies the PBP as biomedical glue outperforming some commercial products for applications in hemostasis performance, accelerated wound healing, and sealing of defected organs, anticipating to be useful as a tissue adhesive and sealant.

Intratumoral synthesis of transformable metal-phenolic nanoaggregates with enhanced tumor penetration and retention for photothermal immunotherapy.

Rationale: Effective photothermal therapy (PTT) remains a great challenge due to the difficulties of delivering photothermal agents with both deep penetration and prolonged retention at tumor lesion spatiotemporally. Methods: Here, we report an intratumoral self-assembled nanostructured aggregate named FerH, composed of a natural polyphenol and a commercial iron supplement. FerH assemblies possess size-increasing dynamic kinetics as a pseudo-stepwise polymerization from discrete nanocomplexes to microscale aggregates. Results: The nanocomplex can penetrate deeply into solid tumors, followed by prolonged retention (> 6 days) due to the in vivo growth into nanoaggregates in the tumor microenvironment. FerH performs a targeting ablation of tumors with a high photothermal conversion efficiency (60.2%). Importantly, an enhanced immunotherapeutic effect on the distant tumor can be triggered when co-administrated with checkpoint-blockade PD-L1 antibody. Conclusions: Such a therapeutic approach by intratumoral synthesis of metal-phenolic nanoaggregates can be instructive to address the challenges associated with malignant tumors.

First Survey of the Pathogenic Fungus Batrachochytrium dendrobatidis in Wild Populations of the Yunnan Caecilian (Ichthyophis bannanicus) in Guangxi, China.

Batrachochytrium dendrobatidis (Bd), which causes chytridiomycosis, mainly infects Anura and Caudata but is poorly known in Gymnophiona. We conducted a survey of Bd in the Yunnan caecilian (Ichthyophis bannanicus) and found that 6 of 71 samples (8.4%) tested positive for Bd. To our knowledge, this is the first detection of Bd in wild I. bannanicus.

Roles of tissue plasminogen activator and its inhibitor in proliferative diabetic retinopathy.

AIM: To investigate the role of tissue plasminogen activator (t-PA) and plasminogen activator inhibitor (PAI) in proliferative diabetic retinopathy (PDR) and to discuss the correlations among t-PA, PAI and vascular endothelial growth factor (VEGF) expressions. METHODS: A total of 36 vitreous samples were collected from 36 patients with PDR (PDR group), and 17 vitreous samples from 17 patients with idiopathic macular hole were used as control. The concentrations of t-PA, PAI and VEGF in samples were determined by ELISA method. The correlations among t-PA, PAI and VEGF expressions were discussed. RESULTS: The concentrations of t-PA, PAI and VEGF in the PDR group were significantly higher than those in the control group (P<0.001). The t-PA and PAI expressions were highly correlated with the VEGF expression (P<0.001). CONCLUSION: In addition to VEGF, a variety of bioactive substances, such as t-PA and PAI, are involved in the pathogenesis involved in the angiogenesis of PDR. VEGF can activate t-PA expression, resulting in collagen tissue degradation and angiogenesis. VEGF may also activate the mechanism for endogenous anti-neovascularization.

[The correlation study of the expression of VEGF with t-PA and PAI expression in plasma and intraocular tissue in proliferative diabetic retinopathy].

OBJECTIVE: To evaluate the correlation between the expression of VEGF with t-PA and PAI expression in plasma aqueous humor and vitreous of proliferative diabetic retinopathy (PDR). METHODS: It was an experimental study. The concentrations of VEGF t-PA and PAI in plasma, aqueous humor and vitreous body in PDR and normal group were detected by ELISA. RESULTS: The levels of VEGF (53.37 ng/L) and PAI (8.00 µg/L) in the plasma of PDR patients were higher than control group, and there was significant statistically difference between them (Z = -3.437, -5.816; P < 0.01). The levels of t-PA (24.32 µg/L) in plasma of PDR patients and control group was no statistically difference between them (Z = -1.715, P = 0.086). The levels of VEGF (335.00 ng/L) t-PA (5.70 µg/L) and PAI (0.63 µg/L) in the aqueous humor of PDR patients were higher than control group, and there was statistically difference between them (Z = -4.805, -1.967, -4.018; P < 0.05). The levels of VEGF (691.69 ng/L) t-PA (13.05 µg/L) and PAI (4.01 µg/L) in the vitreous of PDR patients were higher than control group , and there was statistically difference between them (Z = -2.807, -2.642, -2.230;P < 0.05). Compare the plasma aqueous humor and vitreous of PDR patients. The levels of VEGF is: vitreous>aqueous humor>plasma. The levels of t-PA is: plasma>vitreous>aqueous humor. The levels of PAI is: plasma and vitreous>aqueous humor. The expression of VEGF was highly correlated with t-PA and PAI in plasma aqueous humor and vitreous of PDR (P < 0.05). CONCLUSIONS: VEGF PAI in plasma, VEGF t-PA PAI in aqueous humor and vitreous were increases. The expression of VEGF was positive correlated with t-PA and PAI in plasma aqueous humor and vitreous of PDR.